Project Summary Optogenetics is a powerful tool for relating brain function to behavior because it enables cell- type specific manipulation of neurons with millisecond temporal precision and artifact-free neural recordings. Such capabilities are particularly needed in studies using non-human primates (NHPs), where sophisticated behavioral techniques are commonly employed but neurophysiological tools have lagged those used in other model species. While the use of optogenetics in NHPs has grown rapidly in recent years, the full power of the technique requires the ability to perform large-scale, bi-directional study of neural circuits. Systems to achieve this have become widely used in other animal models, particularly mice, while there have been limited systems implemented in NHPs. In this proposal, a large-scale, high-density, and stable optoelectric neural interface (smart dura) for large brains will be developed and validated in macaques, for the first time. This novel interface enables simultaneous electrical recording from 4096 electrodes and optical stimulation in 4096 sites over about 5 cm2 of cortex, which is more than two orders of magnitude higher than the state-of-the-art technology. As opposed to existing surface electrocorticography (ECoG) electrode arrays, the proposed neural interface is in the form of an artificial dura that monolithically embeds electrical recording and optical stimulation functionalities such that it can permanently replace the native dura as a chronic, seamless neural interface, while maintaining the natural cranial pressure. Therefore, this novel design combines the best of passive/static artificial dura windows and functional surface electrode arrays in one unified platform. The proposed smart dura enables long-term recording, provides new opportunities for creating sophisticated closed-loop stimulation and recording paradigms, and advances the development of new stimulation-based therapies. The smart dura can be implanted as a stable port into large brains and consists of high-density recording electrodes as well as optical micro light sources all embedded in a hybrid biocompatible polymer platform. In this project, a novel fabrication process will be designed to implement the proposed large-scale (5 cm2) smart dura in two stages of: i) Fabricating high-density transparent electrical smart dura for electrophysiology recording and external optical access (transparent electric dura: transparent e- dura), enabled by high resolution interconnects (300 nm features). ii) The optoelectric dura (oe- dura) consisting of high-density recording electrodes and embedded micro light emitting diodes (LEDs). In each stage of the device development, the neural interface will be tested in two hemispheres of two monkeys, with large optogenetic expression of activating opsin (ChR2) in sensorimotor cortex via electrophysiology recording, behavior, and imaging. The proposed smart dura will greatly enhance the opportunities for closed-loop optogenetic experiments in macaques, which can serve as a powerful tool for understanding brain function and for developing novel therapeutic interventions that can be translated to humans. After successful demonstration of the smart dura in this proposal, the results can be extended in future to i) develop even larger interfaces that cover the whole brain for translational use ii) integrate recording, stimulation, processing, communication and power-transfer electronics into the smart dura to enable tetherless chronic neural interfacing with freely-moving subjects.